Over the last decades, numerous papers have appeared—and still are appearing—that describe concentrations in tissues in an effort to predict the efficacy of an antimicrobial agent based on these concentrations and MICs for microorganisms. A common method is to use measurements of concentrations in tissue homogenates, comparing these with values derived from the corresponding blood samples and on that basis draw conclusions with respect to the potential clinical use of the drug. This approach is not justifiable for a number of reasons that includes both pharmacokinetic as well as pharmacodynamic causes. This way of presenting data with the derived conclusions is often misleading and may ultimately be harmful in patient care.

The pharmacodynamic properties governing the activities of antibiotics against intracellular Staphylococcus aureus are still largely undetermined. Sixteen antibiotics of seven different pharmacological classes (azithromycin and telithromycin [macrolides]; gentamicin [an aminoglycoside]; linezolid [an oxazolidinone]; penicillin V, nafcillin, ampicillin, and oxacillin [β-lactams]; teicoplanin, vancomycin, and oritavancin [glycopeptides]; rifampin [an ansamycin]; and ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin [quinolones]) have been examined for their activities against S. aureus (ATCC 25923) in human THP-1 macrophages (intracellular) versus that in culture medium (extracellular) by using a 0- to 24-h exposure time and a wide range of extracellular concentrations (including the range of the MIC to the maximum concentration in serum [ C _max ; total drug] of humans). All molecules except the macrolides caused a net reduction in bacterial counts that was time and concentration/MIC ratio dependent (four molecules tested in detail [gentamicin, oxacillin, moxifloxacin, and oritavancin] showed typical sigmoidal dose-response curves at 24 h). Maximal intracellular activities remained consistently lower than extracellular activities, irrespective of the level of drug accumulation and of the pharmacological class. Relative potencies (50% effective concentration or at a fixed extracellular concentration/MIC ratio) were also decreased, but to different extents. At an extracellular concentration corresponding to their C _max s (total drug) in humans, only oxacillin, levofloxacin, garenoxacin, moxifloxacin, and oritavancin had truly intracellular bactericidal effects (2-log decrease or more, as defined by the Clinical and Laboratory Standards Institute guidelines). The intracellular activities of antibiotics against S. aureus (i) are critically dependent upon their extracellular concentrations and the duration of cell exposure (within the 0- to 24-h time frame) to antibiotics and (ii) are always lower than those that can be observed extracellularly. This model may help in rationalizing the choice of antibiotic for the treatment of S. aureus intracellular infections.

Antibiotics used by general practitioners frequently appear in adverse-event reports of drug-induced hepatotoxicity. Most cases are idiosyncratic (the adverse reaction cannot be predicted from the drug's pharmacological profile or from pre-clinical toxicology tests) and occur via an immunological reaction or in response to the presence of hepatotoxic metabolites. With the exception of trovafloxacin and telithromycin (now severely restricted), hepatotoxicity crude incidence remains globally low but variable. Thus, amoxicillin/clavulanate and co-trimoxazole, as well as flucloxacillin, cause hepatotoxic reactions at rates that make them visible in general practice (cases are often isolated, may have a delayed onset, sometimes appear only after cessation of therapy and can produce an array of hepatic lesions that mirror hepatobiliary disease, making causality often difficult to establish). Conversely, hepatotoxic reactions related to macrolides, tetracyclines and fluoroquinolones (in that order, from high to low) are much rarer, and are identifiable only through large-scale studies or worldwide pharmacovigilance reporting. For antibiotics specifically used for tuberculosis, adverse effects range from asymptomatic increases in liver enzymes to acute hepatitis and fulminant hepatic failure. Yet, it is difficult to single out individual drugs, as treatment always entails associations. Patients at risk are mainly those with previous experience of hepatotoxic reaction to antibiotics, the aged or those with impaired hepatic function in the absence of close monitoring, making it important to carefully balance potential risks with expected benefits in primary care. Pharmacogenetic testing using the new genome-wide association studies approach holds promise for better understanding the mechanism(s) underlying hepatotoxicity.